Method for stabilizing arylcarboxylic acid, stabilizer thereof and aqueous solution containing stabilized arylcarboxylic acid

ABSTRACT

A method for stabilizing an arylcarboxylic acid, which comprises adding a heterocyclic base to the arylcarboxylic acid or a pharmacologically acceptable salt thereof, a stabilizer thereof and an aqueous solution containing a stabilized arylcarboxylic acid. According to the stabilization method of the present invention, arylcarboxylic acid and pharmacologically acceptable salts thereof, particularly pranoprofen, can be stabilized at every temperature range, particularly at lower temperatures, thereby making the production of an aqueous solution to be used as an eye drop, nasal drop, ear drop and the like possible.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a method for stabilizing arylcarboxylicacid, which is an acidic compound and which has an antiinflammatoryactivity, or a pharmacologically acceptable salt thereof, a stabilizerthereof and an aqueous solution containing a stabilized arylcarboxylicacid.

BACKGROUND OF THE INVENTION

Arylcarboxylic acid and pharmacologically acceptable salts thereof havebeen known to be extremely superior antiinflammatory agents. However,said arylcarboxylic acids, particularly pranoprofen, diclofenac andbromfenac, are associated with a problem that they become unstable in anaqueous solution.

Arylcarboxylic acid and pharmacologically acceptable salts thereof havebeen also known to be stabilized by adding an antioxidant, by adjustingthe pH, concentration and ionic strength thereof, by shutting out thelight, and the like. These methods, nevertheless, cannot providesufficient stability at lower temperatures.

Thus, an aqueous solution has not been provided which contains anarylcarboxylic acid or a pharmacologically acceptable salt thereof,particularly pranoprofen, dicrofenac or bromfenac, and which hassufficient stability at lower temperatures.

While WO9632941 A1 discloses pranoprofen combined with an organic amine,it does not disclose the heterocyclic base to be used in the presentinvention.

SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide a methodfor stabilizing an arylcarboxylic acid and a pharmacologicallyacceptable salt thereof.

Another object of the present invention is to provide a stabilizer of anarylcarboxylic acid and a pharmacologically acceptable salt thereof,which contains a heterocyclic base.

Yet another object of the present invention is to provide an aqueoussolution containing a solubilized arylcarboxylic acid and a heterocyclicbase.

According to the present invention, it has now been found that theaddition of a heterocyclic base to an arylcarboxylic acid or apharmacologically acceptable salt thereof leads to successfulstabilization thereof, particularly pranoprofen, at every temperaturerange, particularly at low temperatures.

Thus, the present invention provides the following.

(1) A method for stabilizing an arylcarboxylic acid or apharmacologically acceptable salt thereof, which comprises adding aheteroryclic base of the formula (II):

 wherein

A and A′ are each a carbon atom or a nitrogen atom;

X is a carbon atom or a nitrogen atom;

Y and Z are each a carbon atom or Y and Z may combinedly form CH;

R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ may be the same or different and each is ahydrogen atom, a halogen, a carboxyl group, an optionally substitutedlower alkyl group, an optionally substituted cycloalkyl group, anoptionally substituted acyl group, an optionally substituted aryl groupor an optionally substituted heterocyclic group,

wherein R⁴ and R⁵ may form a 4- to 6-membered heterocyclic group withthe adjacent nitrogen atom and X, and R⁶ and R⁷ may form a 4- to6-membered heterocyclic group with the adjacent Y and Z, provided thatwhen X is a nitrogen atom, R⁵ is void; and

is a single bond or a double bond, provided that when A is a carbonatom, Y and Z are each CH and is a double bond, and when A is a nitrogenatom, Y and Z combinedly form CH and is a single bond,

 to an arylcarboxylic acid of the formula (I):

L¹—R¹ COOH  (I)

 wherein

L¹ is an optionally substituted heterocyclic group or aryl group havingnot more than 14 carbon atoms; and

R¹ is an optionally substituted alkyl group having not more than 4carbon atoms or a single bond,

 or a pharmacologically acceptable salt thereof.

(2) The method of (1) above, wherein the heterocyclic base is a purinebase of the formula (III):

 wherein

R⁹, R¹⁰ and R¹¹ may be the same or different and each is a hydrogen atomor an optionally substituted alkyl group,

 or a pharmacologically acceptable salt thereof.

(3) The method of (2) above, wherein the purine base is at least onecompound selected from the group consisting of caffeine, theobromine andtheophylline.

(4) The method of (1) above, wherein the heterocyclic base is apyridonecarboxylic acid of the formula (IV):

 wherein

X is as defined above; and

R¹², R¹³, R¹⁴ and R¹⁵ may be the same or different and each is ahydrogen atom, a halogen, a carboxyl group, an optionally substitutedlower alkyl group, an optionally substituted cycloalkyl group, anoptionally substituted acyl group, an optionally substituted aryl groupor an optionally substituted heterocyclic group;

wherein R¹² and R¹³ may form a 4- to 6-membered heterocyclic group withthe adjacent nitrogen atom and X, and R¹⁴ and R¹⁵ may form a 4- to6-membered heterocyclic group with the adjacent carbon atom, providedthat when X is a nitrogen atom, R¹³ is void,

 or a pharmacologically acceptable salt thereof.

(5) The method of (4) above, wherein the pyridonecarboxylic acid is atleast one compound selected from the group consisting of lomefloxacin,norfloxacin, ofloxacin, enoxacin, ciprofloxacin and tosufloxacin.

(6) The method of (1) above, wherein the arylcarboxylic acid is at leastone compound selected from the group consisting of ibuprofen,diclofenac, 2-naphthoic acid, 2-naphthylacetic acid, 2-naphthoxyaceticacid, bromfenac, pranoprofen, salicylic acid, aspirin, flufenisal,ibufenac, alclofenac, flurbiprofen, ketoprofen, naproxen, mefenamicacid, niflumic acid, metiazinic acid, protizinic acid, clonixin,indomethacin and fenclozic acid.

(7) The method of (1) above, wherein the heterocyclic base is added in aproportion of 0.001-5 parts by weight per 100 parts by weight of thearylcarboxylic acid.

(8) A stabilizer of an arylcarboxylic acid or a pharmacologicallyacceptable salt thereof, which comprises, as an active ingredient, aheterocyclic base of the formula (II):

 wherein

A and A′ are each a carbon atom or a nitrogen atom;

X is a carbon atom or a nitrogen atom;

Y and Z are each a carbon atom or Y and Z may combinedly form CH;

R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ may be the same or different and each is ahydrogen atom, a halogen, a carboxyl group, an optionally substitutedlower alkyl group, an optionally substituted cycloalkyl group, anoptionally substituted acyl group, an optionally substituted aryl groupor an optionally substituted heterocyclic group,

wherein R⁴ and R⁵ may form a 4- to 6-membered heterocyclic group withthe adjacent nitrogen atom and X, and R⁶ and R⁷ may form a 4- to6-membered heterocyclic group with the adjacent Y and Z, provided thatwhen X is a nitrogen atom, R⁵ is void; and

is a single bond or a double bond, provided that when A is a carbonatom, Y and Z are each CH. and is a double bond, and when A is anitrogen atom, Y and Z combinedly form CH and is a single bond.

(9) The stabilizer of (8) above, wherein the heterocyclic base is apurine base of the formula (III):

 wherein

R⁹, R¹⁰ and R¹¹ may be the same or different and each is a hydrogen atomor an optionally substituted alkyl group,

 or a pharmacologically acceptable salt thereof.

(10) The stabilizer of (9) above, wherein the purine base is at leastone compound selected from the group consisting of caffeine, theobromineand theophylline.

(11) The stabilizer of (8) above, wherein the heterocyclic base is apyridonecarboxylic acid of the formula (IV):

 wherein

X is as defined above; and

R¹², R¹³, R¹⁴ and R¹⁵ may be the same or different and each is ahydrogen atom, a halogen, a carboxyl group, an optionally substitutedlower alkyl group, an optionally substituted cycloalkyl group, anoptionally substituted acyl group, an optionally substituted aryl groupor an optionally substituted heterocyclic group;

wherein R¹² and R¹³ may form a 4- to 6-membered heterocyclic group withthe adjacent nitrogen atom and X, and R¹⁴ and R¹⁵ may form a 4- to6-membered heterocyclic group with the adjacent carbon atom, providedthat when X is a nitrogen atom, R¹³ is void,

 or a pharmacologically acceptable salt thereof.

(12) The stabilizer of (11) above, wherein the pyridonecarboxylic acidis at least one compound selected from the group consisting oflomefloxacin, norfloxacin, ofloxacin, enoxacin, ciprofloxacin andtosufloxacin.

(13) The stabilizer of (8) above, wherein the arylcarboxylic acid is atleast one compound selected from the group consisting of ibuprofen,diclofenac, 2-naphthoic acid, 2-naphthylacetic acid, 2-naphthoxyaceticacid, bromfenac, pranoprofen, salicylic acid, aspirin, flufenisal,ibufenac, aldlofenac, flurbiprofen, ketoprofen, naproxen, mefenamicacid, niflumic acid, metiazinic acid, protizinic acid, clonixin,indomethacin and fenclozic acid.

(14) The stabilizer of (8) above, wherein the heterocyclic base iscontained in a proportion of 0.001-5 parts by weight per 100 parts byweight of the arylcarboxylic acid.

(15) An aqueous solution containing an arylcarboxylic acid or apharmacologically acceptable salt thereof stabilized by the method of(1) above and a heterocyclic base of the formula (II):

 wherein

A and A′ are each a carbon atom or a nitrogen atom;

X is a carbon atom or a nitrogen atom;

Y and Z are each a carbon atom or Y and Z may combinedly form CH;

R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ may be the same or different and each is ahydrogen atom, a halogen, a carboxyl group, an optionally substitutedlower alkyl group, an optionally substituted cycloalkyl group, anoptionally substituted acyl group, an optionally substituted aryl groupor an optionally substituted heterocyclic group,

wherein R⁴ and R⁵ may form a 4- to 6-membered heterocyclic group withthe adjacent nitrogen atom and X, and R⁶ and R⁷ may form a 4- to6-membered heterocyclic group with the adjacent Y and Z, provided thatwhen X is a nitrogen atom, R⁵ is void; and

is a single bond or a double bond, provided that when A is a carbonatom, Y and Z are each CH and is a double bond, and when A is a nitrogenatom, Y and Z combinedly form CH and is a single bond.

(16) The aqueous solution of (15) above, wherein the heterocyclic baseis a purine base of the formula (III):

 wherein

R⁹, R¹⁰ and R¹¹ may be the same or different and each is a hydrogen atomor an optionally substituted alkyl group,

 or a pharmacologically acceptable salt thereof.

(17) The aqueous solution of (16) above, wherein the purine base is atleast one compound selected from the group consisting of caffeine,theobromine and theophylline.

(18) The aqueous solution of (15) above, wherein the heterocyclic baseis a pyridonecarboxylic acid of the formula (IV):

 wherein

X is as defined above; and

R¹², R¹³, R¹⁴ and R¹⁵ may be the same or different and each is ahydrogen atom, a halogen, a carboxyl group, an optionally substitutedlower alkyl group, an optionally substituted cycloalkyl group, anoptionally substituted acyl group, an optionally substituted aryl groupor an optionally substituted heterocyclic group;

wherein R¹² and R¹³ may form a 4- to 6membered heterocyclic group withthe adjacent nitrogen atom and X, and R¹⁴ and R¹⁵ may form a 4- to6-membered heterocyclic group with the adjacent carbon atom, providedthat when X is a nitrogen atom, R¹³ is void,

 or a pharmacologically acceptable salt thereof.

(19) The aqueous solution of (18) above, wherein the pyridonecarboxylicacid is at least one compound selected from the group consisting oflomefloxacin, norfloxacin, ofloxacin, enoxacin, ciprofloxacin andtosufloxacin.

(20) The aqueous solution of (15) above, wherein the arylcarboxylic acidis at least one compound selected from the group consisting ofibuprofen, diclofenac, 2-naphthoic acid, 2-naphthylacetic acid,2-naphthoxyacetic acid, bromfenac, pranoprofen, salicylic acid, aspirin,flufenisal, ibufenac, alclofenac, flurbiprofen, ketoprofen, naproxen,mefenamic acid, niflumic acid, metiazinic acid, protizinic acid,clonixin, indomethacin and fenclozic acid.

(21) The aqueous solution of any one of the above (15) to (20), which isan eye drop.

(22) The aqueous solution of any one of the above (15) to (20), which isa nasal drop.

(23) The aqueous solution of any one of the above (15) to (20), which isan ear drop.

DETAILED DESCRIPTION OF THE INVENTION

The stabilizing method of the present invention comprises the additionof a stabilizer containing a heterocyclic base as an active ingredientto an arylcarboxylic acid, which is an acidic compound and which has anantiinflammatory activity, or a pharmacologically acceptable saltthereof. For example, a heterocyclic base is added to an arylcarboxylicacid or a pharmacologically acceptable salt thereof.

To be specific, an arylcarboxylic acid and a heterocyclic base aredissolved in water and the pH thereof is adjusted with boric acid,acetic acid, phosphoric acid and the like, which is followed bylyophilization where necessary.

While the pH varies depending on the kind of arylcarboxylic acid, it isgenerally 5-9, preferably about 6-8.

Said heterocyclic base may be any as long as it has the followingformula (II):

wherein

A and A′ are each a carbon atom or a nitrogen atom;

X is a carbon atom or a nitrogen atom;

Y and Z are each a carbon atom or Y and Z may combinedly form CH;

R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ may be the same or different and each is ahydrogen atom, a halogen, a carboxyl group, an optionally substitutedlower alkyl group, an optionally substituted cycloalkyl group, anoptionally substituted acyl group, an optionally substituted aryl groupor an optionally substituted heterocyclic group,

wherein R⁴ and R⁵ may form a 4- to 6-membered heterocyclic group withthe adjacent nitrogen atom and X, and R⁶ and R⁷ may form a 4- to6-membered heterocyclic group with the adjacent Y and Z, provided thatwhen X is a nitrogen atom, R⁵ is void; and

is a single bond or a double bond, provided that when A is a carbonatom, Y and Z are each CH and is a double bond, and when A is a nitrogenatom, Y and Z combinedly form CH and is a single bond.

The alkyl of the “optionally substituted lower alkyl group” has 1 to 6carbon atoms, and may be a linear or branched one, such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl,isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, neohexyl and thelike.

The cycloalkyl of the “optionally substituted cycloalkyl group” has 3 to9 carbon atoms, and is exemplified by cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and the like.

The substituents of the above-mentioned lower alkyl group and cycloalkylgroup include lower alkyl group, halogen and the like.

The lower acyl of the “optionally substituted lower acyl group” may be,for example, formyl group, acetyl group, propionyl group, butyryl group,isobutyryl group, valeryl group, benzoyl group, naphthoyl group, toluoylgroup, salicyloyl group and the like.

The above-mentioned acyl may be substituted by suitable substituentswhich may be the same or different, such as

lower alkyl (e.g., methyl, ethyl, propyl, etc.);

lower alkoxy (e.g., methoxy, ethoxy, propoxy, etc.);

lower alkylthio (e.g., methylthio, ethylthio, etc.);

lower alkylamino (e.g., methylamino, ethylamino, propylamino and thelike);

cyclo(lower)alkyl such as cyclo(C₃-C₆)alkyl (e.g., cyclopentyl,cyclohexyl and the like);

cyclo(lower)alkenyl such as cyclo(C₃-C₆)alkenyl (e.g., cycloxenyl,cyclohexadienyl and the like);

halogen (e.g., fluorine, chlorine, bromine and iodine);

amino; amino protecting group; hydroxy; protected hydroxy; cyano; nitro;carboxy; protected carboxy; sulfo; sulfamoyl; imino; oxo;

amino(lower)alkyl (e.g., aminomethyl, aminoethyl and the like),carbamoyloxy, hydroxy(lower)alkyl (e.g., hydroxymethyl, 1- or2-hydroxyethyl, 1- or 2- or 3-hydroxypropyl and the like); and the like.

The aryl of the “optionally substituted aryl group” is exemplified byphenyl, naphthyl and the like, with preference given to naphthyl.

The heterocyclic group of the optionally substituted heterocyclic groupmay contain, besides the carbon atom, at least one hetero atom selectedfrom the group consisting of a nitrogen atom, sulfur atom and oxygenatom, as the atom constituting the ring, and may be a saturated orunsaturated, heteromonocyclic or heteropolycyclic group.

The preferable heterocyclic groups are the following:

3- to 6-membered unsaturated heteromonocyclic group having 1 to 4nitrogen atoms, such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl,pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g.,4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl and thelike), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl and the like),triazinyl (e.g., 1,2,4-triazinyl and the like), and the like;

3- to 7-membered saturated heteromonocyclic group having 1 to 4 nitrogenatoms, such as pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl,homopiperazinyl, and the like;

saturated heteropolycyclic group having 1 to 4 nitrogen atoms, such asquinuclidinyl and the like;

unsaturated heteropolycyclic group having 1 to 5 nitrogen atoms, such asindolyl, isoindolyl, 3H-indolyl, indolizinyl, benzoimidazolyl, quinolyl,isoquinolyl, indazolyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, benzotriazolyl, tetrazolo-pyridazinyl (e.g.,tetrazolo[1,5-b]pyridazinyl and the like), pteridinyl, carbazolyl,phenanthrinidyl, acridinyl, perimidyl, and the like;

3- to 6-membered unsaturated heteromonocyclic group having 1 to 3nitrogen atoms and 1 or 2 oxygen atoms, such as oxazolyl, isooxazolyl,oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl and the like), and the like;

3- to 6-membered saturated heteromonocyclic group having 1 to 3 nitrogenatoms and 1 or 2 oxygen atoms, such as morpholinyl, sydnolyl, and thelike;

unsaturated condensed heterocyclic group having 1 to 3 nitrogen atomsand 1 or 2 oxygen atoms, such as benzofurazanyl, benzoxazolyl,benzoxazinyl, benzoxadiazolyl, and the like;

3- to 6-membered unsaturated condensed heterocyclic group having 1 to 3nitrogen atoms and 1 or 2 sulfur atoms, such as thiazolyl, isothiazolyl,thiadiazolyl (e.g., 1,,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl and the like), and the like;

3- to 6-membered saturated heteromonocyclic group having 1 to 3 nitrogenatoms and 1 or 2 sulfur atoms, such as thiazolidinyl and the like;

unsaturated condensed heterocyclic group having 1 to 3 nitrogen atomsand 1 or 2 sulfur atoms, such as benzothiazolyl, benzothiadiazolyl, andthe like;

3- to 6-membered unsaturated heteromonocyclic group having 1 oxygenatom, such as furyl, pyranyl and the like;

3- to 6-membered unsaturated heteromonocyclic group having 1 or 2 sulfuratoms, such as thienyl, dihydrothienyl, and the like;

unsaturated condensed heterocyclic group having 1 or 2 sulfur atoms,such as benzothienyl and the like; and the like.

The aryl group and heterocyclic group are optionally substituted by oneor more substituents selected from the group consisting of hydroxylgroup, halogen atom, aliphatic alkyl group, aromatic alkyl group,aliphatic carboxylic acid group, aromatic carboxylic acid group,aliphatic carboxylate group, aromatic carboxylate group, aliphatic ethergroup, aromatic ether group, aliphatic alcohol group, aromatic alcoholgroup, aliphatic aldehyde group, aromatic aldehyde group, aliphaticamino group, aromatic amino group and the like, which are optionallysubstituted by halogen atom.

The 4- to 6membered ring formed by R⁴ and R⁵ with the adjacent nitrogenatom and X, and the 4- to 6-membered heterocyclic ring formed by R⁶ andR⁷ with the adjacent Y and Z may be, for example, thienyl group, furylgroup, pyrrolyl group, imidazolyl group, pyrazolyl group, thiazolylgroup, isothiazolyl group, oxazolyl group, isooxazolyl group,oxadiazolyl group, thiadiazolyl group, triazolyl group, pyridyl group,pyrazinyl group, pyrimidinyl group, pyridazinyl group, triazinyl group,dithiazolyl group, dioxolanyl group (e.g., 1,3-dioxolanyl group),dithiolyl group, pyrrolidinyl group, thiaziadinyl group, dithiaziadinylgroup, morpholinyl group, oxazinyl group, thiazinyl group, piperazinylgroup, piperidinyl group, pyranyl group, thiopyranyl group and the like.

The above-mentioned heterocyclic base is specifically exemplified by apurine base having a purine skeleton and a pyridonecarboxylic acidhaving a pyridine skeleton or pyridazine skeleton.

The purine base is a compound of the formula (II) wherein A is anitrogen atom, Y and Z may combinedly form CH and is a single bond. Itis represented by the formula (III):

wherein

R⁹, R¹⁰ and R¹¹ may be the same or different and each is a hydrogen atomor an optionally substituted alkyl group,

and exemplified by caffeine, theobromine, theophylline and saltsthereof.

The pyridonecarboxylic acid is a compound of the formula (II) wherein Ais a carbon atom, Y and Z are each CH and is a double bond. It isrepresented by the formula (IV):

wherein

X is as defined above; and

R¹², R¹³, R¹⁴ and R¹⁵ may be the same or different and each is ahydrogen atom, a halogen, a carboxyl group, an optionally substitutedlower alkyl group, an optionally substituted cycloalkyl group, anoptionally substituted acyl group, an optionally substituted aryl groupor an optionally substituted heterocyclic group;

wherein R¹² and R¹³ may form a 4- to 6-membered heterocyclic group withthe adjacent nitrogen atom and X, and R¹⁴ and R¹⁵ may form a 4- to6-membered heterocyclic group with the adjacent carbon atom, providedthat when X is a nitrogen atom, R¹³ is void.

Examples of the pyridonecarboxylic acid include norfloxacin:[1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylicacid], ofloxacin:[(±)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-[1,2,3-de]-1,4-benzoxazine-6-carboxylicacid], enoxacin:[1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylicacid], cinoxacin:[1-ethyl-1,4-dihydro-4-oxo-[1,3]-dioxolo[4,5-g]cinnoline-3-carboxylicacid], ciprofloxacin:[1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylicacid], sparfloxacin:[5-amino-1-cyclopropyl-7-(cis-3,5-dimethyl-1-piperazinyl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylicacid], tosufloxacin:[(±)-7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1-naphthyridine-3-carboxylicacid], fleroxacin:[6,8-difluoro-1-(2-fluoroethyl)-1,4dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylicacid], levofloxacin:[(−)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylicacid], lomefloxacin:[1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylicacid],5,8-dihydro-8-ethyl-2-(1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidinecarboxylicacid,7-(3-amino-1-pyrrolidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,1-cyclopropyl-6-fluoro-7-(3-methylamino-1-pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,7-(3-amino-3-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid and the like, and salts thereof and the like.

The pharmacologically acceptable salts of purine base andpyridonecarboxylic acid include, for example, acid addition salts withinorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acidand the like, organic acid such as acetic acid, lactic acid, succinicacid, methanesulfonic acid, maleic acid, malonic acid, gluconic acid andthe like, or amino acid such as aspartic acid, glutamic acid and thelike; metal salts such as sodium salt, potassium salt and the like; andthe like.

The arylcarboxylic acid to be used for the stabilization of the presentinvention may be any compound as long as it has the following formula(I):

L¹—R¹ COOH  (I)

wherein

L¹ is an optionally substituted heterocyclic group or aryl group havingnot more than 14 carbon atoms; and

R¹ is an optionally substituted alkyl group having not more than 4carbon atoms or a single bond.

The heterocyclic group in the optionally substituted heterocyclic grouphaving not more than 14 carbon atoms may be exemplified by thosementioned above, and the substituents of said heterocyclic group arealso exemplified by those mentioned above.

The aryl of the “optionally substituted aryl group having not more than14 carbon atoms” may be exemplified by those mentioned above, and thesubstituents of said aryl group are also exemplified by those mentionedabove.

The alkyl of the “optionally substituted alkyl group having not morethan 4 carbon atoms” may be, for example, a linear or branched one suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and thelike.

Examples of the arylcarboxylic acid include naphthoic acid-relatedcompounds, salicylic acid-related compounds, phenylacetic acid-relatedcompounds, pyrazolone-related compounds, anthranilic acid-relatedcompounds, indoleacetic acid-related compounds, fenclozic acid-relatedcompounds and salts thereof and the like.

Examples of the naphthoic acid-related compounds include 2-naphthoicacid, 2-naphthylacetic acid, 2-naphthoxyacetic acid and the like.

Examples of the salicylic acid-related compounds include salicylic acid,aspirin, flufenisal, ethenzamide, benorylate and the like.

Examples of the phenylacetic acid-related compounds include ibufenac,alclofenac, flurbiprofen, ketoprofen, naproxen, ibuprofen, bromfenac,pranoprofen, namoxylate, fenoprofen and the like.

Examples of the pyrazolone-related compounds include aminopyrine,phenylbutazone, azapropazone, cinopentazone and the like.

Examples of the anthranilic acid-related compounds include mefenamicacid, niflumic acid, diclofenac, metiazinic acid, protizinic acid,clonixin, flufenamic acid, ketoprofen and the like.

Examples of the indoleacetic acid-related compounds includeindomethacin, intrazole and the like.

The amount of the heterocyclic base to be added to the arylcarboxylicacid or a pharmacologically acceptable salt thereof is preferably about0.001-5 parts by weight per 100 parts by weight of the arylcarboxylicacid or pharmacologically acceptable salt thereof.

The stabilizer of the arylcarboxylic acid and a pharmacologicallyacceptable salt thereof contains a heterocyclic base as an activeingredient, and the amount thereof is about the same as the amountmentioned above.

The solvent to be used for the aqueous solution of the present inventionmay be, for example, purified water, particularly distilled water forinjection. The concentration of the active ingredient of the aqueoussolution, i.e. arylcarboxylic acid, can be markedly increased by aheterocyclic base, preferably to 0.1-10 (w/v)%.

The heterocyclic base to be used for the aqueous solution of the presentinvention may be those mentioned above.

Said aqueous solution may contain various additives as appropriate, suchas buffer, isotonizing agent, solubilizer, antiseptic, thickener,chelating agent, aromatic and the like.

Examples of the buffer include phosphate buffer, borate buffer, citratebuffer, tartrate buffer, acetate buffer, amino acid and the like.

Examples of the isotonizing agent include sugars such as sorbitol,glucose, mannitol and the like, polyhydric alcohols such as glycerol,propylene glycol and the like, salts such as sodium chloride and thelike, and the like.

Examples of the solubilizer include non-ionic surfactants such aspolyoxyethylenesorbitan monoolate, polyoxyethyleneoxystearic acidtriglyceride, polyethylene glycol, polyoxyethylene hydrogenated castoroil and the like, and the like.

Examples of the antiseptic include quaternary ammonium salts such asbenzalkonium chloride, benzethonium chloride, cetylpyridinium chlorideand the like, p-hydroxybenzoates such as methyl p-hydroxybenzoate, ethylp-hydroxybenzoate, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate andthe like, benzyl alcohol, phenethyl alcohol, sorbic acid, salts thereof,thimerosal, chlorobutanol, sodium dehydroacetate and the like.

Examples of the thickener include polyvinylpyrrolidone,hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose, salts thereof andthe like.

Examples of the chelating agent include sodium edetate, citric acid andthe like.

Examples of the aromatic include 1-menthol, borneol, camphor, eucalyptusoil and the like.

The aqueous solution of the present invention is used as an eye drop,nasal drop or ear drop. When it is used as an eye drop, its pH isgenerally adjusted to about 3.5-8.5, preferably about 6-7, when it isused as a nasal drop, its pH is generally adjusted to about 3.5-8.5,preferably about 6-7, and when it is used as an ear drop, its pH isgenerally adjusted to about 3.5-8.5, preferably about 6-7.

While the method for producing the aqueous solution of the presentinvention varies depending on the kind of a desired solution, a knownmethod can be used to produce such aqueous solution.

When the aqueous solution of the present invention is used as an eyedrop, for example, the dose thereof need only be sufficient toeffectively suppress an inflammation in the eye, and may vary accordingto symptoms, the kind of inflammation, the patients (human or animal) inneed of said solution and the like. A typical dose is 20-200 μL,preferably 50-100 μL, which may be administered 1 to 12 times a day.

The present invention is described in more detail by way of Examples andExperimental Examples, which should not be construed as limiting theinvention.

Experimental Example 1

Stabilization of Pranoprofen-1

Solutions (Examples 1-3 below) of 0.5 w/v % pranoprofen wererespectively charged in 5 ml colorless glass ampoules, and allowed tostand at 80° C. for 1 week and 2 weeks, at 60° C. for 1 week and 2weeks, and at 4° C. for 1 week. The percentage of residual pranoprofenin the ampoules after standing was determined by high performance liquidchromatography. The results are shown in Table 1. The values in theTable are relative to the amount of pranoprofen when it was prepared,which was taken as 100.

TABLE 1 residual pranoprofen (%) temperature-period w/o additionnorfloxacin ofloxacin enoxacin 80° C.-1W 95.4 91.0 99.5 96.7 80° C.-2W93.0 85.0 100.4 95.9 60° C.-1W 98.7 98.0 99.8 99.2 60° C.-2W 98.5 93.898.8 98.4  4° C.-1W 87.5 99.8 99.9 99.2

Experimental Example 2

Stabilization of Pranoprofen-2

Solutions (Example 4) of 0.5 w/v % pranoprofen, containing boric acid(1.6 w/v%), caffeine (0.3 w/v %) and sterile purified water (appropriateamount) were respectively charged in 5 ml colorless glass ampoules, andallowed to stand at 80° C. for 2 weeks, at 60° C. for 1 week, 2 weeksand 4 weeks, and at 4° C. for 1 week and 1 month. The percentage ofresidual pranoprofen in the ampoules after standing was determined byhigh performance liquid chromatography. The results are shown in Table2. The values in the Table are relative to the amount of pranoprofenwhen it was prepared, which was taken as 100.

TABLE 2 residual pranoprofen (%) temperature-period w/o additioncaffeine 80° C.-2W 91.9 94.2 60° C.-1W 100.1 101.3 60° C.-2W 99.2 100.960° C.-4W 96.7 99.5  4° C.-1W 95.0 100.8  4° C.-1M 93.5 97.8

As is evident from the results shown in Table 1 and Table 2, pranoprofenwas markedly stabilized against heat by the addition of ofloxacin,enoxacin and caffeine. The decomposition of pranoprofen which occurs atlow temperatures was significantly suppressed by norfloxacin, ofloxacin,enoxacin and caffeine.

EXAMPLE 1

An eye drop having the following formulation was prepared.

pranoprofen 1.0 g norfloxacin 0.6 g boric acid 3.2 g sodium hydroxideappropriate amount sterile purified water appropriate amount totalamount 200 ml (pH 7)

EXAMPLE 2

An ear drop having the following formulation was prepared.

pranoprofen 1.0 g ofloxacin 0.6 g boric acid 3.2 g sodium hydroxideappropriate amount sterile purified water appropriate amount totalamount 200 ml (pH 7)

EXAMPLE 3

A nasal drop having the following formulation was prepared.

pranoprofen 1.0 g enoxacin 0.6 g phosphoric acid 0.1 g sodium hydroxideappropriate amount sterile purified water appropriate amount totalamount 200 ml (pH 7)

EXAMPLE 4

An eye drop having the following formulation was prepared.

pranoprofen 0.5 g caffeine 0.3 g boric acid 1.6 g sterile purified waterappropriate amount total amount 100 ml (pH 7)

EXAMPLE 5

An eye drop having the following formulation was prepared.

pranoprofen 0.1 g ofloxacin 0.3 g boric acid 1.8 g sorbic acid 0.1 gsterile purified water appropriate amount total amount 100 ml (pH 7)

EXAMPLE 6

An eye drop having the following formulation was prepared.

pranoprofen 0.1 g enoxacin 0.3 g boric acid 1.8 g benzalkonium chloride0.002 g sodium citrate 0.1 g sterile purified water appropriate amounttotal amount 100 ml (pH 7)

EXAMPLE 7

An eye drop having the following formulation was prepared.

pranoprofen 0.1 g caffeine 0.3 g boric acid 1.8 g benzalkonium chloride0.002 g sterile purified water appropriate amount total amount 100 ml(pH 7)

EXAMPLE 8

An ear drop having the following formulation was prepared.

pranoprofen 1.0 g ofloxacin 0.6 g phosphoric acid 0.1 g sodium hydroxideappropriate amount sterile purified water appropriate amount totalamount 200 ml (pH 7)

According to the stabilization method of the present invention,arylcarboxylic acid and pharmacologically acceptable salts thereof,particularly pranoprofen, can be stabilized at every temperature range,particularly at lower temperatures, thereby making the production of anaqueous solution to be used as an eye drop, nasal drop, ear drop and thelike possible.

This application is based on application Ser. No. 21805/1997 filed inJapan, the content of which is incorporated hereinto by reference.

What is claimed is:
 1. A method for stabilizing an carboxylic acid or a pharmacologically acceptable salt thereof, which comprises adding a heterocyclic base of the formula (II):

wherein A and A′ are each a carbon atom or a nitrogen atom; X is a carbon atom or a nitrogen atom; Y and Z are each a carbon atom or Y and Z taken together optionally form CH; R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, wherein R⁴ and R⁵ optionally form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X, and R⁶ and R⁷ optionally form a 4- to 6-membered heterocyclic group with the adjacent Y and Z, provided that when X is a nitrogen atom, R⁵ is void; and is a single bond or a double bond, provided that when A is a carbon atom, Y and Z are each CH and is a double bond, and when A is a nitrogen atom, Y and Z combinedly form CH and is a single bond, to an carboxylic acid of the formula (I): L¹—R¹COOH  (I) wherein L¹ is an optionally substituted heterocyclic group having not more than 14 carbon atoms; and R¹ is an optionally substituted alkyl group having not more than 4 carbon atoms or a single bond, or a pharmacologically acceptable salt thereof.
 2. The method of claim 1, wherein the heterocyclic base is a purine base of the formula (III):

wherein R⁹, R¹⁰ and R¹¹ are the same or different and each is a hydrogen atom or an optionally substituted alkyl group, or a pharmacologically acceptable salt thereof.
 3. The method of claim 2, wherein the purine base is at least one compound selected from the group consisting of caffeine, theobromine and theophylline.
 4. The method of claim 1, wherein the heterocyclic base is a pyridonecarboxylic acid of the formula (IV):

wherein X is a carbon atom or a nitrogen atom; and R¹², R¹³, R¹⁴ and R¹⁵ are the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group; wherein R¹² and R¹³ optionally form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X, and R¹⁴ and R¹⁵ optionally form a 4- to 6-membered heterocyclic group with the adjacent carbon atom, provided that when X is a nitrogen atom, R¹³ is void, or a pharmacologically acceptable salt thereof.
 5. The method of claim 4, wherein the pyridonecarboxylic acid is at least one compound selected from the group consisting of lomefloxacin, norfloxacin, ofloxacin, enoxacin, ciprofloxacin and tosufloxacin.
 6. The method of claim 1, wherein the carboxylic acid is at least one compound selected from the group consisting of pranoprofen, niflumic acid, metiazinic acid, protizinic acid, clonixin, indomethacin and fenclozic acid.
 7. The method of claim 1, wherein the heterocyclic base is added in a proportion of 0.001-5 parts by weight per 100 parts by weight of the arylcarboxylic acid. 